This invention relates to a method of treatment of breast cancer in susceptible warm-blooded female animals including humans using a therapy comprising administering an antiandrogen to such animals after the hormone output of their ovaries has been blocked by surgical or chemical means. The invention also includes pharmaceutical compositions useful for such treatment and pharmaceutical kits containing such compositions. In its most preferred aspect, this invention relates to treatment of breast cancer in warm-blooded animals by parenterally administering an LH-RH agonist or LH-RH antagonist, in association with orally administering an antiandrogen and orally administering an antiestrogen and orally administering an inhibitor of sex steroid biosynthesis.
While various investigators have been studying hormone-dependent breast and prostate cancer, none have proposed the combination therapy of this invention.
A. V. Schally et al., Cancer Treatment Reports, 68, (No. 1) 281-289 (1984), summarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostate tumors by use of analogues of luteinizing hormone-releasing hormones, the so-called LH-RH agonists and suggest that LH-RH analogs and/or antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Pro. Natl. Acad. Sci. USA, 80, 1459-1462 (1983), disclose reduction of estrogen-dependent mammary tumors in rats and mice by use of an LH-RH agonist, [D-Trp.sup.6 ]LH-RH or of two specific antagonists.
In U.S. Pat. No. 4,071,622, it is disclosed that use of certain LH-RH agonists causes regression of DMBA-induced mammary carcinoma in rats.
In U.S. Pat. No. 4,472,382, it is disclosed that certain LH-RH agonists alone may be useful in the treatment of prostate adenocarcinoma and hormone-dependent mammary tumors. While the use of certain LH-RH agonists and an antiandrogen are disclosed for treatment of prostate adenocarcinoma and benign prostate hypertrophia, there is no disclosure or suggestion of the present invention.
Some clinical improvement in premenopausal women with breast cancer by use of the two LH-RH agonists, Buserelin and Leuprolide, is also reported by H. A. Harvey et al. "LH-RH analogs in the treatment of human breast cancer", LH-RH and Its Analogs--A New Class of Contraceptive and Therapeutic Agents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E. Hafez, eds) Lancester, MTP Press, (1984) and by J. G. M. Klijn et al. "Treatment with luteinizing hormone releasing hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer", Lancet, 1, 1213-1216 (1982).
Treatment of advanced breast cancer with aminoglutethimide after therapy with the antiestrogen, Tamoxifen is disclosed by A. V. Buzdar et al., Cancer, 50, 708-1712 (1982).
H. Flax et al., Lancet, 1204-1207, (1973), suggest some women's breast cancers are androgen-dependent.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that use of a combination therapy of an LH-RH agonist (Buserelin) and an antiandrogen (Anandron) to treat advanced prostate cancer in previously untreated patients effects simultaneous elimination of androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 99-1007 (1983), disclose the treatment of prostate cancer by the combined administration of an LH-RH agonist and an antiandrogen. Labrie et al. disclose animal and clinical data in support of the proposition that the combined LH-RH/antiandrogen treatment neutralizes the stimulatory influence of all androgens on the development and growth of androgen-dependent prostatic cancer.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of antiestrogens such as meso-3,4-bis(3'-hydroxyphenyl)hexane inhibits MCF7 human breast tumor cells. In fact, the inhibitory activity of the antiestrogen was antagonized by estradiol. cells. In fact, the inhibitory activity of the antiestrogen was antagonized by estradiol.
H. Mouridsen et al,. Cancer Treatment Review 5, 131-141, (1978), disclose that Tamoxifen, an antiestrogen is effective in remission of advanced breast cancer in about 30% of the patients treated.
J. G. M. Klijn et al., (J. Steroid Biochem, Vol. 20 (No. 6B), 1381 (1984), disclose the combined use of the antiestrogen, Tamoxifen, and the LH-RH agonist, Buserelin, for treatment of breast cancer is known, but objective remission of such cancers remains low (35%).